Obesity and Weight Management in Primary Care

obesity

and weight management in primary care

“From Samoa to the Steppes, from Sao Paolo to Sydney every country faces a potential public health disaster i f it fails to take decisive measures not only to introduce better management but far more effective preventive measures to hhlt the slide we have seen accelerating over the past 25 years”. Professor W.P.T. James Chairman, International Obesity Task Force, 1999

obesity

and weight management in primary care

Colin Waine OBE, FRCGP,FRCPath Director of Health Programmes and Primary Care Development Sunderland Health Authority Sunderland, UK Foreword by Nick Bosanquet Professor of Health Policy Imperial College London, UK

Blackwell Science

0 2002 by Blackwell Science Ltd a Blackwell Publishing Company EDITORIAL OFFICES Osney Mead, Oxford OX2 OEL, UK Tel: +44 (0)1865 206206 Blackwell Science, Inc., 350 Main Street, Malden, MA 02148-5018, USA Tel: + I 781 388 8250 Blackwell Science Asia Pty, 54 University Street, Carlton, Victoria 3053, Australia Tel: +61 (0)3 9347 0300 Blackwell Wissenschafis Verlag, Kurfurstendamm 57, 10707 Berlin, Germany Tel: +49 (0)30 32 79 060

The right of the Author to be identified as the Author of this Work has been asserted in accordance with the Copyright, Designs and Patents Act 1988. All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, except as permitted by the UK Copyright, Designs and Patents Act 1988, without the prior permission of the publisher. First published 2002 Catalogue records for this title are available from the British Library and Library of Congress ISBN 0-632-06514-1 Set in 9/11.5pt Sabon Text layout and design by Designers Collective Limited Printed and bound in Great Britain by Ashford Colour Press Ltd, Gosport, Hants For further information on Blackwell Science, visit our website: www.blackwell-science.co.uk

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Contents Foreword . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . vii Preface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ix Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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1 Introductionand overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 2 Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 3 Causesofobesity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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4 The autocrine. paracrine and endocrine functions of adipose tissue . . . . . . . . . . .21 5 Obesity-a disease in its own right! . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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6 Beneficial effects of modest weight loss . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41 7 Management in clinical practice: a patient orientated approach . . . . . . . . . . . . . . 47 .

8 Drug treatment in the management of obesity . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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9 The place of surgery in the management of obesity . . . . . . . . . . . . . . . . . . . . . . . .

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10 Theeconomicconsequencesofobesity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87 11 Preventionofobesity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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12 Childhoodobesity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Appendix 1: Healthy eating . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101 Appendix 2: Characteristics of successful weight management programmes . . .104 Appendix3:Factsonfat . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 106 Appendix4:BMIcharts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 108 Appendix 5: The Milan Declaration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111 Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 113

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Forew ord Risk factor is a term which strikes uneasily at the conscience of health professionals. In socially deprived areas almost every second patient bears witness to the possible impact of risk factors such as obesity and smoking on their health and even survival: but in the pressure of dayto-day consultations there is rarely time to do more than treat symptoms rather than deal with causes. Dr Colin Waine writes from experience as a GP and as a leader in primary care programmes. He is one of a small group of innovators from the North East who have influenced primary care in the region and well beyond it. Obesity and Weight Management in Primary Care is a useful summary of the evidence on the disease of obesity which impacts both on quality of life and on ill health. The text gives a careful review of the links to long-term illness, especially diabetes and cardiovascular disease. It also sets realistic targets for making a difference. There is no need to aim for ideal weight - even a reduction of 5-10 kilos could make a real difference in reducing later ill health. The problem remains how this is to be a priority in a world where the short-term and the urgent press in. There has to be realistic recognition of the time and effort required to get results in this field and this is where Dr Waine’s book goes beyond a review of the evidence. He sets out a practical programme for a PCO based on a specialist centre for weight management which stresses communication and the shared setting of goals as well as a detailed programme for diet and exercise. He also sets out the potentially valuable role of new drug therapies in adding to the range of options for effective programmes. In 1996 16 per cent of men and 18 per cent of women were obese - and with change in diet and more sedentary lifestyle the problem is set to get worse. Dr Waine also provides evidence on childhood obesity and on economic costs of obesity. He has set the item firmly on the agenda for PCOs and PCTs. Nick Bosanquet Professor of Health Policy, Imperial College, London

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Preface Obesity is undoubtedly the major nutritional disorder of the western world. In fact, it has such a major impact on mortality, morbidity and quality of life that it most certainly merits consideration as a disease in its own right. All western nations are facing a burgeoning of the problems associated with obesity. The UK, for example, is facing a veritable epidemic as the prevalence doubled between 1980 and 1991. While the bad news is that the prevalence of obesity is rising, the good news is that achieving and maintaining relatively modest weight loss can have a major beneficial impact of the risk of developing those common and lifethreatening conditions such as type 2 diabetes, ischaemic heart disease and certain cancers of which it is so often the precursor. Obesity is not just a matter of gluttony or sloth; it results from complex interactions between genetic and environmental factors, some of which are beyond conscious individual human control. If we are really intent on improving the health of the nation, then halting the current epidemic of obesity must be high on our agenda. To do so will require a combination of public health and individual approaches and the obvious place for the latter is primary care. In this book I have tried to emphasize the importance of taking obesity seriously - as a disease in its own right and of managing it as such. The fact that we no longer need to strive for the well nigh unachievable goal of ideal body weight should make the task of tackling obesity less daunting for both patients and professionals. Hopefully, what follows will help them to success.

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Ac know ledg ernent s My grateful thanks to Professor W.P.T. James for permission to include material from his article ‘A Public Health Approach to the Problem of Obesity’ in the chapter dealing with prevention, and to Tam Fry of the Child Growth Foundation for permission to use the BMI Charts which appear in Appendix 4 and for introducing me to the ‘Cole Calculator’. Mrs Jean Scott, Mrs Karen Mould, Miss Johanna-Maria Deahl and particularly Mrs Anna Sperring have been of immense help in preparing the manuscript and Marcela Holmes and Gina Almond of Blackwell Science have been unfailingly courteous and encouraging.

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Introduction and overview

In 1976 a Department of Health and Social Security/Medical Research Council group concluded that ‘We are unanimous in our belief that obesity is a hazard to health and a detriment to wellbeing. It is common enough to constitute one o f the most important medical and public health problems of our time whether we judge importance by a shorter expectation of life, increased morbidity, or cost to the community in terms of both money and anxiety.’ (James 1976) Twenty-five years on from then, the position has, in fact, worsened. Obesity is a major medical problem, yet it is trivialized in the media and marginalized by the Health Service. The World Health Organization (WHO), despite its historical focus on malnutrition and starvation, has for the first time recognized the problem of overnutrition. In 1998, the WHO said ‘The epidemic projections for the next decade are so serious that public health action is urgently required’ (WHO 19981, and again in 2000 (WHO 2000) it called for urgent action to combat the growing epidemic of obesity which now affects developing and industrialized countries alike. The United Kingdom (UK) is currently experiencing an epidemic of overweight and obesity. Over 6 million people in the UK are obese. The prevalence of serious obesity doubled in Britain between 1980 and 1991 and is continuing to increase. Over the past 20 years in all affluent nations there has been an explosion of overweight individuals who will increase the health care demands for diabetes, hypertension, heart disease, gall bladder disease, some forms of cancer and osteoarthritis over the coming decades (Bray 1999). Even in the developing countries a pattern of rapidly escalating obesity and its comorbidities is becoming apparent in certain sections of society. Prentice (Prentice 2000) has cited the Gambia as an example, pointing out that rural poverty and malnutrition now vie with the diseases of urban prosperity-obesity and type 2 diabetes-for scarce health care resources. Current projections predict that the rise ic obesity and type 2 diabetes in the developing world will outstrip that of the west; this adding another health burden to countries already beleaguered by famine and disease.

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Ckiariter 1

Obesity is the major nutritional disorder facing westernized civilizations and has become a major economic burden to most developed countries. It accounts for between 4% and 8% of total healthcare expenditure and is assuming increasing importance as a disease entity, with a massive impact on mortality, morbidity and the quality of life of those unfortunate enough to bear its consequences. Currently overweight and obesity may account for as much as 30% of coronary heart disease and 75% of new cases of type 2 diabetes (Jung 1997). However, coronary heart disease and type 2 diabetes are but two of the major conditions associated with obesity-other disabling conditions should not be ignored because obesity contributes to disorders of systems, e.g. cardiovascular and respiratory; to disorders of metabolism, e.g. insulin resistance and hyperlipidaemia; and to the development of site-specific cancers, e.g. colorectal, bilary system, or uterine, as well as cancers of the cervix and ovary. The American Heart Association has recently upgraded obesity from a contributing risk factor to a major risk factor for coronary heart disease, thereby acknowledging that obesity is a lifelong disease that is becoming a dangerous epidemic with high rates of morbidity and mortality. The fact is that in spite of our imperfect knowledge of all the factors that lead to obesity, people can be helped to lose weight and to maintain weight loss; but achieving this on a large scale will require fundamental changes in the way that society in general and health professionals in particular view the management of obesity. It is not simply a question of gluttony or sloth (Prentice & Jebb 1995). Unfortunately many members of the public and, indeed, many health professionals often view obesity simply as a problem of eating too much and exercising too little, when in fact it is a complex, multifactorial disease of appetite regulation and energy metabolism that involves genetics, physiology, biochemistry and the neurosciences as well as environmental, psychological and cultural factors (Thomas 1995). Obesity, of course, is not increasing because people are consciously trying to gain weight. In fact, millions of people in this country are dieting at any one time; they and many others are struggling to manage their weight to improve their appearance, feel better and become healthier. Obesity is a remarkable disease in terms of the discrimination its victims suffer and the efforts required by an individual for its successful management. Obese people, like people with physical handicaps, wear their problem for all to see at all times; yet, unlike that group, they are held responsible for their condition (Wooley et al. 1979a, 1979b). Prejudice against fat people starts at school, affects their jobs and social opportunities and is so pervasive that it can colour the attitudes of professionals.

Introduction and overview

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In the last few years there has been renewed interest in the use of drugs to aid the successful management of obesity, and attitudes have liberalized to the extent that there is growing acknowledgement that the treatment of obesity, like the treatment of hypertension, may have to be continued over long periods of time. The goals of obesity treatment need to be refocused from weight loss alone to weight management, and success judged more on the effects on the overall health of individuals rather than on the achievement of ideal body weight. Because the increasing prevalence of overweight and obesity represents a most pervasive public health problem, it certainly deserves greater investment in both good quality research and service provision (Glennie et a/. 1997). Although obesity is a serious medical condition and is associated with a wide range of chronic and life-threateningconditions, ‘although obese individuals suffer increased psycho-social problems and a reduced quality of life’, and although the prevalence of obesity has enormous implications for the Health Service, it has not until quite recently attracted the scientific attention which its importance certainly deserves. While the bad news is that the prevalence of obesity is rising, the good news that has emerged over the last few years is that relatively modest weight loss can have a major impact on reducing the risk factors for developing type 2 diabetes, cardiovascular disease and other obesity related conditions (Goldstein 1992). Until quite recently the obese were urged to strive for the achievement of their ideal body weight, which required such massive changes in the eating habits and lifestyle of individuals that for the majority it was doomed to failure. One of the most important findings from recent research into obesity is the benefit to individuals of a 5-10% weight loss in improving their risk profile (James 1996). The fact that it is no longer necessary to strive for the well-nigh unachievable ideal body weight and that the benefits of the 5-10% reduction in weight are so considerable should motivate both doctors and patients to achieve the achievable. Effective weight management does not simply mean organizing a slimming process-it is a completely different concept geared to ensuring that the long-term health of the patient is the key concern. While primary care is the obvious place for managing high risk individuals (see Chapter 7) there is also the need for a massive public health approach to reduce the prevalence of overweight and obesity in the population. Unfortunately a lack of success in treating obesity has led to a sense of frustration among general practitioners and practice nurses. To some extent this has been associated with the setting of unrealistic targets; for the severely obese person, achieving ideal body weight is just not a viable proposition. Obesity is serious health problem which as much deserves a structured approach to its management as do hypertension and diabetes.

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4

ChaDter 1

While diet and exercise will remain crucial to its effective management, drug therapy should certainly be considered in high-risk patients, as should the use of surgery for a limited group of people. No longer should obesity be regarded simply as a cosmetic issue, nor as a moral judgement on those who suffer from it.

References Bennett N., Dodd. T & Flatley, J. (1996) Health Sutvey for England 7993. HMSO, London. Bray, G.A (1999) Obesity: The Threat Ahead. European Congress of Obesity, Germany, p. 42. Glennie, A.M., O’Meara, S., Melville, A,, Sheldon, TA etal. (1997) The treatment and prevention of obesity: a systematic review of the literature. lnternationalJournal of Obesity 21, 715-737. Goldstein, D.J. (1992) Beneficial health effects of modest weight loss. lnternationalJournal of Obesity 16, 397-415. James, W.PT (1976) Research on Obesity: a report of a DHSSIMRC Group. HMSO, London. James, W.PT (1996) The lnternational Obesity Task Force; Obesity at the World Health Organisation. Nutrition, Metabolism and Cardiovascular Disease Supplement 6, 12-1 3. Jung, R.T (1997) Obesity as a disease. British Medical Bulletin 53, 307-321. Prentice, A.M. (2000) Urban obesity in the Gambia. Obesity in Practice 2, 2-5. Prentice, A.M & Jebb, S.A. (1995) Obesity in Britain: Gluttony or Sloth? British Medical Journal 311,437-439. Thomas, PR. (ed.) (1995) Weighing the Options. National Academy Press, Washington Wooley, S.C., Wooley, O.W. & Dyrenforth, S.R. (1979a) Obesity and women Il-A neglected feminist topic. Women’s Studies lnternationalQuaflerly 2, 81-92. Wooley, S.C., Wooley, O.W. & Dyrenforth, S.R. (1979b) Theoretical, practical and social issues in behavioural treatments of obesity. Journal of Applied Behaviour Analysis 12, 3-25. World Health Organization (1998) Prevention and Management of the Global Epidemic of Obesity. Report of the WHO consultation on obesity, Geneva 1997.WH0, Geneva. World Health Organization (2000) Preventing and Managing the Global Epidemic. Report of the WHO Consultation. WHO Technical Report Series 894. Geneva, Switzerland.

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Epidemiology

DEFINITION, CLASSIFICATIONAND IDENTIFICATION It has been traditional to define obesity in terms of a particular individual’s body mass index (BMI). Although this can be criticized on the grounds that differences in weight between individuals are only partly due to variations in body fat, the fact remains that there is a very good correlation between BMI and the percentage of body fat in large populations. Body Mass Index =

weight in,kgs (Height in m)2

The World Health Organization and International Obesity Task Force definitions of obesity are shown in Fig. 2.1. There are, however, drawbacks to using this measurement in clinical practice: 1 It usually requires recourse to tables. 2 Height must be measured accurately because errors are exaggerated by squaring. 3 More importantly it fails to distinguish general from truncal obesity and it is the latter which is related to the presence of a constellation of risk factors including insulin resistance, hyperinsulinaemia, decreased glucose tolerance, decreased HDL cholesterol, elevated LDL cholesterol and triglycerides, and hypertension-often known collectively as syndrome X, the metabolic syndrome, or Reaven’s syndrome. It is today’s people with syndrome X who will be tomorrow’s victims of type 2 diabetes, coronary heart disease and other vascular disorders.

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Ctiapter2

For busy clinicians, waist measurement is emerging as an alternative to calculating BMI (Han et al. 1995). Sex-specific waist measurement in relation to risk can be seen in Fig. 2.2. The waist :hip ratio has been a traditional method of identifying people with prominent truncal obesity, but recent research has shown the value of using the waist circumference alone. This should be measured at half-way between the superior iliac crest and the ribcage in the midaxilliary line. For busy primary care workers, waist measurement is a more practical tool than calculating BMI. The above figures apply to people of Caucasian origin; for people of Asian origin there is a substantial risk for women above 80 cm and men above 88 cm waist circumference. In fact, using BMI alone only has a positive predictive value of central obesity of 64% in men and 84% in women and will therefore miss a considerable number of people at high risk of developing type 2 diabetes and circulatory disorders. The circumference of the waist relates closely to BMI, is the dominant measurement in waist : hip ratio, and reflects the proportion of body fat located intra-abdominally as opposed to subcutaneously (Lean et al. 1995). The simplicity of waist measurement and its relationship to body weight, fat distribution and a clustering of cardiovascular risk factors, suggests that it could well have a place in primary care in identifying the ‘at risk’.

IMPORTANCE OF FAT DISTRIBUTION The distribution of excess adipose tissue is closely linked to the development of the major risk factors associated with obesity. Vague (Vague 1956) pointed out the strong association between android (upper-body or truncal) obesity and the development of type 2 diabetes mellitus. Truncal obesity, sometimes referred to as ‘apple shaped’, is significantly more strongly associated with the development of risk factors than gynoid (gluteo-femoral or ‘pear shaped’) obesity. Android obesity is now recognized as ‘a feature of the syndrome of insulin resistance’ (sometimes known as the metabolic syndrome, syndrome X or Reaven’s syndrome), which includes compensatory hyperinsulinism, dyslipidaemia, hypertension, glucose intolerance, a pro-coagulant tendency

Epidemiology

and accelerated atheroma formation (Reaven 1988).This will be further discussed in Chapter 5 . The importance of waist measurement over BMI is that it does recognize the importance of intra-abdominal fat accumulation and its greater relevance to accompanying risk factors. Figure 2.3 shows the relationship between waist measurement and odds ratio for risk factors. Intra-abdominal fat accumulation is often indicative of a constellation of risk factors which include insulin resistance and hyperinsulinaemia, hypertension, dyslipidaemia (raised total cholesterol), LDL cholesterol and triglycerides and lowered HDL cholesterol which markedly increase an individual’s risk of developing coronary heart disease.

PREVALENCE The prevalence of obesity in a population refers to the percentage of people in that population with excess storage of body fat and it has increased by about 1 0 4 0 % in most developed countries in the past decade. During this period the prevalence in the UK has doubled (Fig. 2.4). In 1996 16% of men and 18% of women were obese and a further 45% of men and 34% of women were overweight. One percent of the population was categorized as severely obese. The Health of the Nation report one year on pointed out that over half of the adult male population and just under half of the adult female population were overweight to a clinically undesirable degree. Men tend to predominate in the category BMI 25-30, whereas there are more women than men who are obese (BMI 3 0 4 0 ) or severely obese (BMI >40). About a quarter of

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Chapter 2

all adults are estimated to be dieting at any one time. Health of the Nation 1992 targeted a reduction in the proportion of obese people (BMI >30)to not more than 6% of men and 8% of women by the year 2005. The growing world epidemic of obesity is shown graphically in Fig. 2.5.

COMORBID CONDITIONS Obesity and overweight are associated with an increased risk of developing type 2 diabetes, hypertension, coronary heart disease, stroke, and gall bladder disease, as well as certain cancers (Jung 1997). In addition, obese people are often discriminated against socially and tend to have low self-esteem. In males the greatest correlation 'is with colorectal cancer, whereas in females it is with endometrial cancer, followed by cancer of the gall bladder and biliary tract. Also, in females, excessive obesity is associated with an increased risk of breast, cervical and ovarian cancers (Lew & Garfinkel 1987). In addition, obesity and overweight contribute to the development of osteoarthritis, breathlessness, dyspepsia, sleep apnoea and venous thromboembolism; they make pregnancy, anaesthesia and surgery more hazardous; and they contribute to psychological distress and low selfesteem (Drug & Therapeutics Bulletin 1998).

Epidemiology

References Anon. (1998) Why and how should adults lose weight. Drug and Therapuetics Bulletin 36 (12). 89-92. Han, TS., Van Leer, E.M.. Seidell, J.C. etal. (1995) Waist circumference action levels in the identification of cardiovascular risk factors-prevalence study in a random sample. British MedicalJournal 311, 1401-1405. Jung, R.T. (1997) Obesity as a disease. British Medical Bulletin 53,307-321. Lew, E.A. & Garfinkel, D. (1987) Variation in mortality by weight among 750,000 men and women. Journal of Chronic Diseases 32,563-576. Reaven, G.M. (1988) Role of insulin resistance in human disease. Diabetes 37, 1595-1 607. Vague, J. (1956) The degree of masculine differentiation of obesities; the factor determining predisposition to diabetes, atherosclerosis, gout and uric calculus disease. American Journal of Clinical Nutrition 4, 2&34.

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Causes of obesity

HEREDITY A review of studies involving more than 10 000 individuals from biological and adoptive relationships. It determined the correlation of BMI for monozygotic and dizygotic twins and for the biological parent-offspring and adoptive-relative pairs. It found a weighted mean BMI correlation of 0.74 for monozygotic twins and 0.32 for dizygotic twin pairs. This corresponds to an estimated hereditibility of between 50% and 90%. In addition the correlations for biological parent-offspring pairs and adoptive pairs were 0.19 and 0.06, respectively. This indicates a relatively minor role for the cultural transmission of obesity.

GENETIC A N D FAMILIAL Studies in Denmark (Stunkard et al. 1986; Sorensen et al. 1989) have given substance to there being a genetic component to obesity; they studied adoptees and twins. Studies of adoptees showed great correlation between their weight and that of their biological, but not their adopted, parents and siblings. Twin studies showed great intrapair correlation coefficients regardless of whether they were reared together or apart. The researchers have postulated that genetic influences on BMI could account for up to 70% of variants. However, this may well be an exaggerated claim since in epidemiological terms the escalating rates of obesity, which affect large sections of the population, have occurred in a relatively constant gene pool. This suggests that the primary causes lie in environmental and behavioural change (Prentice & Jebb 1995). Children of families where one or both parents are obese are certainly at increased risk of becoming obese themselves (Guillaume et al. 1993).

DEMOGRAPHIC FACTORS Increasing obesity is associated with: Increasing age-at least, up to 50-60 years of age in men and women. Gender-women generally have a higher prevalence of obesity, especially when over 50 years of age. Ethnicity-there are large and often unexplained variations between ethnic groups.

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Chapler 3

SOCIO-CULTURAL FACTORS Risk of obesity is associated with social class (Kahn et al. 1991). In England 1994 age standardized prevalence of obesity in women was 12% and 14% in Classes 1 and 2, compared with 22% and 21% in Social Classes 4 and 5. For men the variations are less: prevalence is 10% in Social Class 1, compared with 1 4 % and 13% in Social Classes 4 and 5 . Educational status is also an influence. Women with no educational qualifications show a mean BMI of 26.7kg/m2 compared with 24.6kg/m2 in those educated to A Level and above (Colhoun & Prescott-Clarke 1996). Being married is often associated with an increased chance of becoming obese.

BIOLOGICAL FACTORS While it has been claimed that BMI increases with increasing parity, recent evidence suggests that this contribution is likely to be small-less than 1 kg per pregnancy (Williamson et al. 1994).

BEHAVIOURAL CHANGE FACTORS Physical inactivity There are a number of behavioural influences of which probably decreasing physical activity is of major importance and likely to be the main factor behind age-related weight gain (Prentice & Jebb 1995). As the nation’s epidemic of obesity has occurred during decades of reducing food intake, the implication must be that levels of energy expenditure decline even more rapidly. Support for this view comes from the following evidence. Mechanisms for regulating body weight were evolved historically under conditions of high physical activity. The increasing affluence of the postwar years has been matched by the adoption of increasingly sedentary lifestyles: only 20% of men and 10% of women are currently employed in physically active occupations (Allied Dunbar 1992). Physically active leisure pursuits have been replaced by inactive pastimes. The average person now watches television 26 h a week compared with 1 3 h in the 1960s. The Health Survey for England (Colhoun & Prescott-Clarke 1996) and the Allied Dunbar National Fitness Survey revealed that in the previous month: 30-35% of men had taken fewer than four 20-minute periods of moderate activity;

Causes 01 obesity

80% of men had not walked continuously for two miles; only 20-30% of men had participated in vigorous activity of any type. In a Finnish study (Rissanen et al. 1991) of 1200 adults over a 5-year period it was concluded that physical inactivity was more important than diet as a cause of obesity (See Fig. 3.1). English activity patterns have probably fallen by an average of $00 kcal/day over the past 20 years (James 1995) while food intake has fallen by about 750 kcaUday. The result is a small but sustained imbalance between intake and output which has to be a major contributory factor in the development of the current epidemic of obesity. Declining physical activity has been matched by the adoption of increasingly sedentary lifestyles. The eating of high-fat diets and small, frequent snacks contributes to obesity because they reduce the conscious recognition that food is being eaten and bypass feelings of satiety. In fact, 1g of fat provides more than twice as many calories as the same quantity of carbohydrate or protein. High-fat diets, which are often palatable without inducing feelings of satiety, are certainly contributory. Fat, unlike protein or carbohydrate, induces only a small rise in metabolic rate. ‘Faced by a life circumstance that discourages routine physical effort and activity and that offers a surfeit o f highly palatable high energy and high fat foods in bewildering variety, weight gain is an understandable consequence’ (Hill & Rogers 1998). All of the above information has important messages for the design of weight-loss and weight-maintenance programmes.

Dietary intake During the last 50 years there has been a marked increase in the fat content of the British diet (MAFF 1994) and there is evidence that high fat consumption undermines the mechanisms regulating energy balance. The eating of high-fat diets and small, frequent snacks contribute to obesity because they reduce the conscious recognition that food is being eaten and bypass feelings of satiety. Although dietary studies suggest an association between obesity and high fat consumption, they suffer from the well known unreliability of the recording of food intake. However, a study of 11600 Scottish men and women (Bolton-Smith & Woodward

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Chapter 3

1994) related the prevalence of obesity to the subjects’ intakes of sugars and fat. This study showed quite clearly that the groups consuming the highest proportion of their energy from carbohydrate were much less likely to be obese compared with low sugar, high fat consumers. Laboratory studies lend support to these findings: The observation that the consumption of food is associated with an increase in energy expenditure and oxygen consumption was made by Lavoisier over 200 years ago. This effect is now termed the ‘thermic effect of food’ (or ‘dietary-induced thermogenesis’). There is now experimental evidence to show that the thermic effect of carbohydrate vastly exceeds the thermic effect of fat. Mechanisms for regulating body weight function more effectively on a high carbohydrate, low-fat diet than on a high-fat, low-carbohydrate diet. Carbohydrate balance is accurately regulated by increases in oxidation which are regulated by the autonomic nervous system and help to compensate for excess energy intake. In humans, isotope studies have shown de novo fat synthesis from carbohydrate is a minor process. Fat is less satiating.

Energy expenditure Carbohydrate and fat are, under normal conditions, the main sources of energy for man. Carbohydrate is stored as glycogen in the liver and muscle, while fat is stored as triglyceride in adipose tissue. There is a much closer correlation between energy intake and expenditure with carbohydrate than there is with fat. Total energy expenditure: Resting energy expenditure and unrestricted physical exercise (Schoeller 1990). Basal Metabolic Rate 70%. Thermic Effect of Food 10%. Spontaneous Physical Activity 20%. The above percentages are averages-there are wide personal variations between individuals (Flatt 1998). Basal metabolic rate (BMR) is determined by the free fat mass, the total body mass, age and gender. Thermogenesis (thermic effect of food) is greater after carbohydrate intake than it is after fat intake. Spontaneous physical activity (fidgeting movements) varies considerably between individuals. Factors related to energy expenditure which could contribute to obesity are therefore: Low BMR; Defects in the thermogenic effect of food; Low levels of spontaneous physical activity.

Causes of obesity

DYNAMICS OF WEIGHT GAIN 8 8

8

When energy intake equals energy expenditure, body weight is constant. When intake begins to exceed expenditure even by relatively small amounts, the slide down the slippery slope towards being overweight and, if unchecked, towards obesity, has begun (See Fig. 3.2). After a period of time a new equilibrium is reached and weight tends to plateau.

Metabolic predictors of weight gain Studies on Pima Indians, a race which is exceptionally prone to obesity, suggest that a low resting BMR and low levels of spontaneous physical activity induce a future tendency to obesity (Ravussin et al. 1988). The fact that there is also a familial tendency towards a low BMR suggests that genetic influences could also play a part. Similar familial tendencies towards low levels of spontaneous physical activity have also been demonstrated-again suggesting that genetic influences could be relevant. Spontaneous physical activity is strongly influenced by the sympathetic nervous system.

SYMPATHO-ADRENAL SYSTEM AND OBESITY The sympathetic nervous system (SNS)and the adrenal medulla together make up the sympatho-adrenal system, which has a major role in maintaining homeostasis. Its effects are mediated: Directly by the sympathetic nerves which supply most parts of the body; Indirectly by catecholamines, adrenaline and noradrenaline released from the adrenal medulla. These enter the blood stream and act as hormones at target sites around the body. The SNS can influence the development of obesity by influencing: Food intake; Energy expenditure; Resting BMR; Fat balance.

15

16

Ci-!anler 3

Food intake A high SNS drive inhibits food intake (Bray et al. 1989; Bray 1991). Studies have shown a strong correlation between postprandial suppression of hunger and noradrenaline response-as an indicator of SNS activity.

Energy expenditure In summary, increased SNS actively increases energy expenditure by its action through B1 and B2 adrenergenic receptors and by increasing the thermogenic effect of food.

Resting BMR People with low SNS activity have a lower BMR which could predispose them to obesity, and possibly a higher food intake (see above).

Fat balance Beta-adrenergic blockade in humans leads to a moderate increase in carbohydrate and protein oxidation but a substantial decrease in fat oxidation, which suggests that of all the macronutrients-carbohydrate, fat and protein-the oxidation of fat is most dependent on sympathetic stimulation. Clearly then, any lack of this stimulation will increase the likelihood of obesity.

Alcohol consumption Moderate or heavy alcohol consumption can be associated with a high BMI (Prentice 1995).

Smoking cessation Smoking cessation is an important risk factor for weight gain in either sex (Flagal et al. 1995). In one study, weight gain as a result of smoking cessation averaged 2.8 kg in males and 3.8 kg in females (Williamson et al. 1991). The weight gain results from a decrease in energy expenditure. Each cigarette utilizes 8 kcal by stimulation of the SNS. Smoking also curbs the appetite, which tends to increase after stopping.

Age The risk of obesity for men increases during their late 30s. Women, however, face an increased risk at several stages in their lives: for example after marriage, during pregnancy, during the menopause and at retirement (Sorensen in Department of Health 1995).

Ethnicity The risk of obesity may vary between different ethnic groups. Asian people are at greater risk of developing obesity than Afro-Caribbean

Causes of obesity

and Caucasian people (NHS 1996). Many Asian people have a central body fat distribution and its related comorbidities even when their BMI is not in the obese range. South Asian people are particularly at risk of developing abdominal obesity. There is also an increased prevalence of insulin resistance in this group.

Drugs Certain drugs can increase appetite and promote weight gain. The commonest are anabolic agents, steroids, some oral contraceptives, sulphonylureas, tricyclic antidepressants, lithium, and some benzodiazepines.

Endocrine and hypothalamic causes A number of endocrine and hypothalamic disorders contribute to the development of obesity and are listed in Fig. 3.3. However, these make only a minor contribution to the current epidemic of obesity and therefore are not discussed in any detail. Readers wishing to know more about them are recommended to consult a textbook on endocrinology.

CONCLUSION It is hoped that the foregoing will suggest to the reader that energy balance and the development of obesity are not much more complicated than a simple measure of calories in and calories out. The development of obesity involves complex interactions between gender and environmental influences and at least some of these are

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Chapter 3

mediated via hormones and the autonomic nervous system- largely beyond conscious influence. Therefore it is little wonder that tackling the problems of obesity is so challenging. Perhaps the first key change is for health workers to appreciate the complexity of the problem-that it is not a simple matter of ‘gluttony or sloth’-and begin to treat obese people with the respect and compassion that the complexity of their condition deserves. The influence of the SNS on both energy intake and expenditure has very important implications for the development of drug treatments and the prevention and management of obesity.

References Allied Dunbar (1992) National Fitness Sutvey: a report on activity patterns and fitness levels. Sports Council and Health Education Authority, London. Bolton-Smith, C. & Woodward, M. (1994) Dietary composition and fat,to sugar ratios in relation to obesity. lnternationalJournal of Obesity 18, 820-828. Bray, G.A. (1991) Reciprocal relation between the sympathetic nervous system and food intake. Brain Research Bulletin 27, 517-520, Bray, G.A., York, D.A. & Fisher, J S. (1989) Experimental Obesity: a homeostasis failure due to defective nutrient stimulation of the sympathetic nervous system. Vitamins Hormones 45, 1-125. Colhoun, H. & Prescott-Clarke, P, eds. (1996) Health suwey for England 1994: a sutvey carried out on behalf of the Department of Health, vol. 1 . HMSO, London, p. 1.449. Department of Health (1 995) Obesity: Reversing the lncreasing Problem of Obesity in England. A report from the Nutritional and Physical Activity Task Forces. Flagal, K.M.. Troiano. R.P, Pamuck, E.R. etal. (1995) The influence of smoking cessation on the prevalence of over weight in the United States. New England Journal of Medicine 333,1 165-1 170. Flatt, J.P (1998) Importance of nutrient balance in body weight regulation. Diabetes Metabolism Review 18, 820-828 Guillaume, M., Lapidus, L., Beckers, F et al.(1993) Prevalence of obesity in Belgian Luxembourg. lnternationalJournal of Obesity 17, (suppl. 2). 36. Hill, A.J. & Rogers, PG. (1998) Food intake and eating behaviour. In: Clinical Obesity (eds P G. Kopelman & M. J. Stock ), pp. 86-1 11. Blackwell Science, Oxford. James, W.PT (1995) A Public Health Approach to the problem of obesity. lnternational Journal of Obesity 19 (Suppl. 3), 37-45. Kahn, H.S., Williamson, D.F. & Stevens, J.A. (1991) Race and weight change in US women; the role of socio-economic and marital status. American Journal of Public Health 83, 319-332. Lew, E.A. & Garfinkel. D. (1987) Variation in mortality by weight among 750,000 men and women. Journal of Chronic Diseases 32,563-576. MAFF (1994) Household f o o d Consumption and Expenditure. HMSO, London, 1940-94. NHS CRD (1996) Ethnicity and Health: reviews of literature and guidance for purchasers in the areas of CVD, mental health and haemoglobinopathy. University of York, York, pp. 46-47. Prentice, A.M. (1995) Alcohol and Obesity. lnternationalJournal of Obesity 19 (Suppl. 5), S44-S50.

Causes of obesity

Prentice, A.M. & Jebb, S.A. (1995) Obesity in Britain. gluttony or sloth? British Medical Journal 311, 437-439. Ravussin, E., Lillioja, S., Knowler, W.C. etal. (1988) Reduced rate of energy expenditure as a risk factor for body weight gain. New England Journal of Medicine 318, 467-472. Rissanen, A.M., Heliovaara, M., Knekt, P etal. (1991) Determinants of weight gain and overweight in adult Finns. European Journal of Clinical Nutrition 45, 419-430. Schoeller, D.A. (1990) How accurate is self reported energy intake? Nutrition Review 48, 373-379. Sorensen, TI., Price, R.A., Stunkard, A.J. etal. (1989) Genetics of obesity in adult adoptees and their biological siblings. British Medical Journal 298, 87-90. Stunkard, A.J., Sorensen. TI.. Hanis, C. etal. (1986) An adoption study of human obesity. New England Journal of Medicine 314, 193-1 9813. Williamson, D.F., Madans, J., Anda. R.F. etal. (1991) Smoking cessation and severity of weight gain in a national cohort. New fngland Journal of Medicine 324, 73S745. Williamson, D.F., Madans, J., Pamuk, E. etal. (1994) A prospective study of childbearing and 10 year weight gain in US white women 25-40 years age. lnternational Journal of Obesity 18, 561-569.

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4

The autocrine, paracrine and endocrine functions of adipose tissue

COMPOSITION OF ADIPOSE TISSUE Adipose tissue is a type of loose connective tissue made up of adipocytes surrounded by a matrix of collagen fibres, blood vessels, fibroblasts and immune cells. In the mesentery and subcutaneous tissues it is organized into large lobular structures. There are basically two types of adipose tissue: white and brown, of which white predominates in humans. Brown fat only makes up a small percentage of total body fat; it is more abundant in infants but is present in adults as well. It is mainly located between the scapulas, at the nape of the neck and along the blood vessels in the thorax and abdomen. In brown fat depots the fat cells as well as the blood vessels have an extensive sympathetic innervation, which is in contrast to white fat depots in which there may be innervation of some fat cells but the principal sympathetic innervation is on blood vessels. This extensive sympathetic innervation is responsible for activating dietary induced thermogenesis which in turn plays a part in energy regulation. Reduced sympathetic activation of brown adipose tissue is a feature of most models of obesity (Stock 1998). White adipocytes have only a single large droplet of white fat, whereas brown fat cells contain several small droplets of fat (Gannong 1999).

Cellular lipids The lipids in cells are of two main types: (i) structural lipids, which are an inherent part of the membranes and other parts of cells; and (ii) neutral fat, which is stored in the adipocytes of the fat depots. While neutral fat is mobilized during starvation, structural lipid is preserved. In the non-obese individual, fat depots make up about 15% of body weight in men and 21% in women. Adipose tissue is not an inert mass but is actively involved in metabolism and energy homeostasis as well as having endocrine and paracrine functions. In addition it influences autonomic and immune function (Flier & Spiegelman 1996; Mohammed-Ali et al. 1998).

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Chanter 4

INTERCELLULAR COMMUNICATION This can occur by the following methods: 1 Neural communication, in which neurotransmitters are released a t synaptic junctions. 2 Endocrine communication, in which hormones and growth factors reach cells via the blood stream. 3 Paracrine communication, in which the products of cells diffuse into the extracellular fluid to reach other cells. 4 Autocrine communication, in which cells secrete chemical messengers that bind to receptors on the same cell (Gannong 1999).

SECRETORY ROLE OF ADIPOSE TISSUE Adipocytes, stroma cells and macrophages secrete a range of substances with autocrine, paracrine and endocrine functions (Fig. 4.1). The roles of some of these substances will now 'be briefly outlined, beginning with leptin which is emerging as a hormone of considerable importance, some even comparing its importance to that of insulin.

Functions of adiDose tissue

Leptin Leptin was discovered in 1994 and is secreted mainly by adipose tissue, although low levels have been detected in the placenta, skeletal muscle, gastric and mammary epithelia, and brain (Freidman & Halaas 1998). Circulating levels of leptin are related to body stores of energy and energy balance. They are high in obese individuals and low in lean people. Females tend to have higher leptin levels than males, probably as a result of an inhibitory effect by androgens. Synthesis of leptin is higher in subcutaneous than visceral fat. Deficiency of leptin results in hyperphagia, decreased energy expenditure and morbid obesity (however, in terms of human obesity leptin deficiency is rare). Injection of leptin into the brain reduces food intake and reduces energy storage as fat. These findings led to the concept of leptin as an anti-obesity hormone. However, the high levels of leptin found in obese people clearly do not prevent its development. Also, clinical trials of injected leptin have yielded disappointing results. This has led to the development of the concept of leptin resistance (compare with insulin resistance). It has been found that the CSF levels of leptin are considerably lower than serum levels in obese people (Schwartz et al. 2000). Thus failure to cross the blood-brain barrier could be a contributory factor to leptin resistance. Leptin exerts its effect on the hypothalamus via a signalling system involving neuropeptide Y (NPY) and agouti-related protein (AGRP) which stimulate food intake, and melanocyte-stimulating hormone (MSH) and cocaine- and amphetamine-related transcript which reduce food intake. Thus an imbalance or failure of the signalling system could also be contributory to leptin resistance. It does seem that leptin signals to the brain information about the size of the body’s energy stores and the switch between the fed and fasted states (Flier 1998). Whilst trials of leptin have so far yielded disappointing results, knowledge about its signalling system has stimulated research into manipulating this for therapeutic purposes. It could be that the future of leptin treatment could be more to do with maintaining than achieving weight loss. Leptin has a range of other functions. Deficiency of leptin is associated with a failure of pubertal maturation. It also influences the immune system, being a potent mediator of immune suppresion during fasting (Lord et al. 1998). Leptin also acts on the endocrine system, including the hypothalamw pituitary axis, and influences the production of growth hormone and prolactin. It also activates the SNS and is involved in blood pressure regulation, brain and bone development, haematopoiesis, and wound healing (Ahima & Flier 2000).

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Chapter 4

An alternative hypothesis on the role of leptin is that of controlling the deposition of fat, preventing its harmful accumulation in tissues such as the heart, liver, and kidneys.

Interleukin 6 (IL-6) IL-6 inhibits the lipoprotein lipase activity and increases aromotase activity. In addition it increases the production of free fatty acids and cholesterol by the liver. Levels of IL-6 rise with increasing BMI, especially if this is associated with abdominal obesity. It stimulates hepatic production of C reactive protein.

Tumour necrosis factor

(Y

Tumour necrosis factor (TNF) has been suggested as a possible mediator of insulin resistance in obesity (Ahima & Flier 2000).

Renin-angiotensin system The complete system is secreted by adipocytes. Levels are decreased by fasting and increased by re-feeding. Angiotensin 11, in addition to its role in regulating blood pressure, also increases the secretion of aromatase which in turn favours the conversion of androgens to oestrogens. It could contribute to the relationship between obesity, hypertension, and increased cardiovascular risk, and to the increased risk of breast and endometrial cancer in postmenopausal women.

Plasminogen activator inhibitor (PAI-1) Plasmin (fibrinolysin) is the active component of the plasminogen (fibrinolysin) system. This enzyme lyses fibrinogen with the production of fibrinogen degradation products that inhibit thrombin. Plasmin is formed from its precursor plasminogen, a process which is prejudiced by plasminogen activator inhibitor (PAI-I ) (Gannong 1999). High levels of PAI-1 have been detected following myocardial infarction (Shimomura et al. 1996). While the liver is the main source of PAI1 production, significant amounts are synthesized by adipose tissue and levels increase in direct proportion to visceral obesity. This could be another link between obesity and cardiovascular risk.

Adipsin (complement D) This is a factor in stimulating the synthesis and storage of triglycerides; levels increase in response to human obesity and to feeding (Ahima & Flier 2000).

Functions of adipose tissue

Adiponectin This is secreted exclusively by adipocytes; levels are decreased in obesity, type 2 diabetes and coronary heart disease. It inhibits vascular smoothmuscle proliferation and expression of various adhesion molecules. The lower levels found in obesity could be contributory to the increased risk of CHD (Ahima & Flier 2000).

Steroid hormones Adipose tissue has the ability to metabolize glucorcorticoids and sex steroid hormones (Sliteri 1987). Oestrogens stimulate adipogenesis in the breast and subcutaneous tissue and androgens promote central obesity. Thus they play an important role in determining fat distribution and could influence the development of insulin resistance, type 2 diabetes and increased risk of CHD.

Resistin The discovery of this hormone was first reported in Nature in January 2001 (Steppan et al. 2001). The molecular links between obesity and type 2 diabetes have been elusive, yet the links are strong as 80% of people with type 2 diabetes are obese. One of the fundamental defects in type 2 diabetes is insulin resistance. The increased storage of triglycerides in adipose tissue in obesity is a factor in causing this tissue to be insulin resistant; but how is this linked to insulin resistance in the liver, skeletal muscle and other body tissues? For some time it has been believed that the non-esterified fatty acids secreted by adipocytes play a part: they probably d o so, by substrate competition in skeletal muscle. Tumour necrosis factor secreted by adipocytes could also be a factor in insulin resistance. Now Steppan and colleagues, utilizing the fact that thiazolidinidiones reverse insulin resistance, have discovered another hormone that they have named resistin. By treating a differentiated adipocyte cell line with thiazolidinidiones, they have identified a new messenger which is apparently only expressed by adipocytes. The evidence that resistin is involved in insulin resistance is provocative but as yet only circumstantial (Flier 2001). The experiments by Steppan and colleagues show that resistin suppresses insulin’s ability to stimulate the uptake of glucose by adipocytes. Whether it is able to do this in liver, muscle and other tissue awaits elucidation.

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Chayter 4

References Ahima, R.S. etal. (1996) Role of leptin in the neuroendocrine response to fasting. Nature 382, 250-252. Ahima, R.S. & Flier, J.S. (2000) Adipose tissue as an endocrine organ. Trends in Endocrinology and Metabolism 11 (8), 327-332. Flier, J.S. (1998) Clinical Review 94, What's in a name? In search of leptin's physiologic role. Journal of Clinical Endocrine and Metabolism 83, 1407-141 3. Flier, J.S. (2001) The missing link with obesity? Nature 409, 292-293. Flier, J.S. & Spiegelman, B.M. (1996) Adipogenesis and obesity: rounding out the big picture. Cell 87, 377-389. Friedman, J.M. & Halaas, J.L. (1998) Leptin and the regulation of body weight in mammals. Nature 395, 763-770. Gannong, W. (1999) Review ofMedical Physiology, 19th edn. Appleton & Lange, p. 519. Lord, G.M. etal. (1998) Leptin modulates the T cell immune response and reverses starvation induced irnmunosuppresion. Nature 294, 897-891 Mohammed-Ali, V etal. (1998) Adipose tissue as an endocrine and paracrine organ. lnternationalJournal of Obesity 22, 1145-1 158. Schwartz, M.W.,Woods, S.C., Ponte Jr, D. etal. (2000) Central nervous system control of food intake. Nature 404, 661-671. Shimomura, I., Funahashi, T , Takahashi, M. eta/. (1996) Enhanced expression of PAI-I in visceral fat: possible contributor to vascular disease in obesity. Nature Medicine 2 , 80C803. Sliteri, PK. (1987) Adipose tissue as a source of hormones. Amencan Journal of Clinical Nutrition 5 (Suppl.) (297-282), 13. Steppan, C.M., Bailey, S.T, Bhat, S. etal. (2001) The hormone resistin links obesity to diabetes. Nature 409, 307-312. Stock, M.J. (1998) Energy balance and animal models of obesity. In: Cbnical Obesity (eds P G. Kopelmann & M. J. Stock), pp. 50-72. Blackwell Science, Oxford.

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5

Obesity-a Obesity IS not p s t

disease in its own right! a hedth risk hiit

rl

dtscdse (Jiing K.T.1997)

INTRODUCTION The contribution of obesity to the development of some of the major chronic diseases affecting western civilization is quite staggering. For instance, above a BMI of 35 kg/m2, women have a 93-fold increase in their risk of developing diabetes mellitus, and men a 42-fold increase. It is paradoxical that although the medical profession is willing to recognize and treat the complications of obesity, such as type 2 diabetes, coronary heart disease and hypertension, it has been much less willing to accord obesity the status of a disease in its own right and devote to it the time and attention that it deserves (Fig. 5.1). Given the now proven links with mortality and morbidity, surely the time has come for a different approach-an approach that recognizes the disease of obesity and accords it the degree of attention that is seen as being appropriate for any major chronic condition that threatens the lifespan and the quality of life of those who experience it.

OBESITY AND MORTALITY The Nurses’ Health Study (Manson et al. 1995) has yielded valuable information about the link between overall mortality and morbidity from specific diseases in a cohort of 115 195 women in the USA who were between 35 and 55 years of age when enrolled into the study in 1976. In the 16-year follow-up period there were 4726 deaths, of which: 881 were due to cardiovascular disease;

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Chapter 5

2586 were due to cancer; 1259 were from other causes. In non-smokers the relative risk of death related to body weight was: 1.3 for BMI 25-26.9. 1.6 for BMI 27-28.9. 2.1 for BMI 29-31. It was concluded that 53% of all deaths in women with BMI 229 were directly related to their obesity. Lean women (BMI 24 kg/m2 had a sevenfold excess risk of gallstone disease compared with those with a BMI